Hepatocarcinogenesis represents an ongoing process which could be divided in initiation and promotion followed by neoplastic progression. In the course of promoting phase, focal, primarily hepatocellular basophilic cell populations (HBF), have been identified as early putative precursors of subsequent cell populations including late emerging carcinomas. Our recent studies showed that the change in the normal sex hormonal environment following puls carcinogenic treatment modifies the onset and the development of HBF and the emergence of neoplastic lesions. This led to the hypothesis that androgen/estrogen ratio modulates the incidence of the hepatocellular carcinomas by influencing the promotion of the initiated cells to HBF and neoplasia and possibly the progression in tumor malignancy: the high ratio accelerating while low ratio delaying these processes. Previously we have found that single, low-dose levels of diethylnitrosamine (DEN) were effective to induce focal cellular changes and a broad spectrum of non-neoplastic and neoplastic nodular liver lesions in direct relationship to the dose used. In order to define the histogenesis of hepatocellular carcinomas in the mouse and to test the above hypothesis regarding hormonal role in tumor promotion and neoplastic progression, we intend to evaluate qualitatively and quantitatively the influence of hormonal environment on hepatocellular basophilic foci, hyperplastic nodules, adenomas, and carcinomas. Groups of animals will be gonadectomized at various intervals following initiation. One of two series will receive hormone replacement therapy after given time periods. Gonadectomies will be schedule to coincide with the emergence of basophilic foci, hyperplastic nodules, adenomas, and hepatocellular carcinomas to establish the potential modulating influence of sex hormonal environment upon the development of each of those morphologic entities. Temporal and, more importantly, morphologic development of the nodular liver lesions, identified by their tinctorial characters, cell morphology, and histoid structure, will be monitored throughout the postinitiating phase of hepatocarcinogenesis. Morphometric quantitaion will be conducted by analyzing microscopic images by means of the Hewlett-Packard Digitizer-Computer System using specifically designed statistical program.